Project 2: LKB1/AMPK signaling and Peutz-Jeahers syndrome. The focus of this project is to further elucidate the signal transduction pathways that inhibit hamartomas formation in humans, focusing on the recently discovered role of the LKB1 tumor suppressor in regulating mTOR signaling via the TSC proteins. The LKB1 tumor suppressor is a serine/threonine kinase which directly phosphorylates and activates the AMP-activated protein kinase (AMPK). Through its regulation of AMPK, LKB1 serves as an low energy checkpoint that controls the response of normal cells and tumor cells to conditions of low glucose and low oxygen. We previously showed this effect is due in part to AMPK induced activation of the TSC2 tumor suppressor and subsequent inhibition of mTOR signaling. We speculate that loss of this normal checkpoint on cell growth is not only critically disrupted in hamartomas, but also in a variety of sporadic tumors. Finally, we have found that cells lacking the LKB1/AMPK/TSC2 pathway are uniquely sensitized to apoptosis following energy deprivation. We anticipate that therapeutic interventions exploiting these findings will be of broad utility, given that agents which confer those effects are already in widespread clinical use as anti-diabetic modalities.